Molecular Medicine Israel

Prenatal Exposure to Cannabis Affects the Developing Brain

Children born to moms who smoked or ingested marijuana during pregnancy suffer higher rates of depression, hyperactivity, and inattention

We live in a medicated era. Recent data indicate that more than half of Americans are currently taking prescription drugs. Among pregnant women this number skyrockets to more than 80 percent. One of these women was a 24-year-old from California named Carol, whom I met and befriended through an online drug research forum. After weeks of debilitating morning sickness, persistent pain in her back and hips, and chronic anxiety about becoming a mother, Carol was taking a tranquilizer called alprazolam as needed, plus daily doses of acetaminophen and an anti-nausea drug called metoclopramide.

Carol felt uneasy using the medications. Like many Americans and an even greater proportion of Europeans, Carol (who asked that I not use her surname) favors home remedies over pharmaceutical treatments. “I’ll always choose a tea over a pill,” she says. And so, as she sought relief during her pregnancy, she turned to marijuana.

In the summer of 2007, Carol was surrounded by people touting the wonders of cannabis as a panacea for diseases from depression to glaucoma and myriad ailments in between—including nausea, pain, and anxiety. Worried that her suboptimal diet and poor sleep could be affecting the development of her child, she considered using small amounts of cannabis instead of the multiple prescription medications suggested by her doctor.
“Instead of two or three pills per day, I could have a little bit of pot in the morning,” she recalls thinking at the time, “and everyone agreed it was harmless.” Weighing the options, Carol decided that while she would prefer to consume neither prescription drugs nor cannabis, the latter was the lesser of two evils. “It seemed natural,” she says. Now, with a 10-year-old son who suffers from attention-deficit/hyperactivity disorder and behavioral problems at school, she wonders if the choice she made has come back to haunt her.

Epidemiologists are looking into the concerns of parents such as Carol. Various large-scale longitudinal research projects in both North America and Europe, ranging from several hundred to thousands of subjects, on cannabis use during pregnancy point to a number of potential consequences, including hyperactivity, in children. The problems start early—exposed infants are more likely than unexposed babies to have low birth weights and to spend time in neonatal intensive care. And troubles can last into adulthood. Higher rates of depression and drug abuse are among the health issues most commonly linked with maternal cannabis use.

Research that can address the causal nature of these links is still in its infancy, however. The status of cannabis as a Schedule I substance in the US makes it tough to get approval for experiments. For this and other reasons, research on the incorporation of the drug in Western medicine is relatively new as well. This means that conventional health practitioners receive little, if any, information that they can pass onto their patients, including those considering the use of cannabis during pregnancy.

It’s no wonder, then, that 70 percent of women in the United States believe that there is “slight or no risk of harm” in using cannabis during pregnancy. And about 4 percent of pregnant women in the US report using the drug during gestation, just like Carol. Of expectant moms between the ages of 18 and 25, this number is nearly 7.5 percent. With a growing national and global acceptance of marijuana use, research on the effects of cannabis exposure during pregnancy is more urgent now than ever.

Cannabis and the prenatal brain
Researchers identified cannabinoids as one group of pharmacologically active compounds in marijuana in 1940, but it was another half a century before they confirmed the existence of an endocannabinoid system (ECS). Over the course of about three years in the early 1990s, neuroscientists discovered the first cannabinoid receptor (CB1R) in mammals, cloned both the rat and human variants, and identified a second cannabinoid receptor (CB2R). Later, the first endogenous cannabinoid was identified and named anandamide after the Sanskrit word for bliss.

Researchers have since characterized a second primary endocannabinoid, 2-AG, known to bind these receptors, plus a host of additional endogenous molecules that interact in other ways with the ECS. Scientists have also identified the enzymes that synthesize and degrade these compounds along with a number of additional putative cannabinoid receptors.

Identified as the brain’s most widely expressed G-protein coupled receptor, CB1R acts to regulate body temperature, relay hunger signals, and process sensory input, with a hand in countless other physiological and cognitive states. (See “Your Body Is Teeming with Weed Receptors,” The Scientist, July/August 2017.) Cannabis contains at least 108 exogenous cannabinoids—including Δ9-THC, which binds to CB1R to cause the high associated with the drug—along with dozens of other pharmacologically active compounds, such as the terpenes and flavonoids. These interact with the ECS to cause an altered psychological state, and mediate myriad other effects the drug in both the brain and the body.

When marijuana is ingested or smoked during pregnancy, exogenous cannabinoids enter the blood and cross easily through the placental barrier due to their highly lipophilic nature. Pairing this ready availability with slow pharmacokinetics—active metabolites continue circulating for up to five days depending on dosage and frequency of use—fetal exposure to the active compounds in cannabis is both efficient and prolonged. It should therefore be expected that this exposure can profoundly influence the development of the ECS.

To date, the three largest longitudinal studies of the children of women who smoked marijuana once a week or more during their pregnancies have identified remarkably consistent outcomes during early development and through young adulthood. In infants, these include increased impulsivity, hyperactivity, and delinquent behaviors, as well as memory dysfunction and decreased IQ scores. During adolescence and early adulthood, fetal cannabis exposure has been linked to persistent reduction in memory and concentration, higher rates of drug use, and an increased incidence of hyperactivity, signs of depression, and psychotic and schizophrenic-like symptoms. These mental health issues are further evidenced by increased reports from both parents and schoolteachers of problematic behavior and delinquency in cannabis-exposed kids.

One of the three large-scale projects, the Ottawa Prenatal Prospective Study, which began following approximately 700 pregnant cannabis users in 1978, has tracked nearly 200 of the offspring from the neonatal period into adulthood, and has identified persistent effects ranging from changes in cortical function to higher rates of drug abuse even in maturity, compared with controls. In men, for example, regular use of marijuana as well as daily tobacco use are both more than twice as likely for those exposed to cannabis in the womb. Data on adults from the two other longitudinal studies—the Generation R study in the Netherlands that is currently tracking nearly 8,000 children and the Maternal Health Practices and Child Development Study at the Western Psychiatric Institute and Clinic in Pittsburgh that is following 580 teenagers—have yet to emerge. But with the persistent and significant changes already seen at multiple ages across nations, spanning economic and social strata, more links between human health and maternal cannabis use would not be surprising.

The nature of the relationship remains unclear, however. Moreover, quantifying marijuana intake is riddled with challenges—the potency of cannabis, as well as the ratio of various active cannabinoids that it contains, is extremely variable, for example—so researchers cannot yet say with confidence how doses of the drug influence these correlations. Now, researchers in the laboratory are linking observations concerning mental health with biological mechanisms involved in cannabis use to get a better handle on the risks of using the drug while pregnant.

Exogenous cannabinoids in an endogenous system
To root out the cellular and molecular mechanisms that might underlie the epidemiological patterns seen in humans exposed to cannabis in utero, researchers are turning to experiments with rodents. Researchers now know that the ECS plays a significant role in the development of the central nervous system, and perturbations to this system in developing mice and rats are associated with lasting disruptions to cell differentiation and neuronal migration, critical steps in the formation of a functional brain. CB1Rs are present in the human cerebrum by the first weeks of the second trimester, and many studies have shown that CB1R knockout mice show significant behavioral problems….

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